Abstract:

A method of detecting an accessory cancer lesion, comprising an
administration step wherein indocyanine green is administered to a living
body, an irradiation step wherein a target organ suspected of having
cancer is surgically exposed and irradiated with excitation light of
indocyanine green, an imaging step wherein a near-infrared fluorescence
intensity distribution image from the excited indocyanine green in the
target organ is obtained, and an identification step wherein an area
having the near-infrared fluorescence in the intensity distribution
image, excluding the area detected in preoperative examination or
intraoperative macroscopic observation, is identified as an accessory
cancer lesion.

Claims:

1. A method of detecting an accessory cancer lesion, comprisingan
administration step wherein indocyanine green is administered to a living
body,an irradiation step wherein a target organ suspected of having
cancer is surgically exposed and irradiated with excitation light of
indocyanine green,an imaging step wherein a near-infrared fluorescence
intensity distribution image from the excited indocyanine green in the
target organ is obtained,and an identification step wherein an area
having the near-infrared fluorescence in the intensity distribution
image, excluding the area detected in preoperative examination or
intraoperative macroscopic observation, is identified as an accessory
cancer lesion.

2. The method of detecting an accessory cancer lesion according to claim 1
wherein the preoperative examination is by x-ray imaging, nuclear
magnetic resonance imaging, or ultrasonographic imaging of the target
organ.

3. The method of detecting an accessory cancer lesion according to claim 1
wherein the indocyanine green is administered through intravenous
injection in the administration step.

4. The method of detecting an accessory cancer lesion according to claim 1
wherein the imaging step is carried out 1 to 10 days after the
administration step.

5. The method of detecting an accessory cancer lesion according to claim 1
wherein the indocyanine green used in the administration step is neither
complexed with a high density lipoprotein nor bound to antibodies against
proteins that are specifically present in the accessory lesion.

6. The method of detecting an accessory cancer lesion according to claim 1
wherein the cancer is primary liver cancer or metastatic liver cancer.

7. The method of detecting an accessory cancer lesion according to claim 1
wherein the living body is a living body of human or non-human mammal.

8. A method of treating cancer wherein an area containing at least one
accessory lesion identified by the method of detecting an accessory
cancer lesion according to claim 1 is shrunk, destroyed or resected.

9. The method of treating cancer according to claim 8 wherein the main
cancer lesion detected in the preoperative examination or the
intraoperative macroscopic observation is shrunk, destroyed, or resected
along with the accessory lesion area.

11. The accessory cancer lesion detection agent according to claim 10
wherein the accessory lesion is present in an area where no lesion is
detected by x-ray imaging, nuclear magnetic resonance imaging, or
ultrasonographic imaging, or through macroscopic observation.

12. The accessory cancer lesion detection agent according to claim 10
wherein the indocyanine green is neither complexed with a high density
lipoprotein nor bound to antibodies against proteins that are
specifically present in the accessory lesion.

14. The accessory cancer lesion detection agent according to claim 10 for
use in detection 1 to 10 days after its administration to the living
body.

15. The accessory cancer lesion detection agent according to claim 14
wherein the living body is a living body of human or non-human mammal.

16. A composition for detecting an accessory cancer lesion comprising the
accessory cancer lesion detection agent according to claim 10, and
distilled water.

17. A data collection method comprisingcomparing a near-infrared
fluorescence intensity distribution image obtained by irradiating a
target organ of a living body into which indocyanine green has been
administered with excitation light of indocyanine green,with a cancer
lesion distribution image obtained by the use of x-rays, nuclear magnetic
resonance or ultrasound on the target organ, before administering the
indocyanine green, andcollecting the data of an area detected in the
near-infrared fluorescence intensity distribution image but not in the
cancer lesion distribution image as data of accessory cancer lesion area.

18. The data collection method according to claim 17 wherein the
near-infrared fluorescence intensity distribution image of the target
organ into which indocyanine green has been administered through
intravenous injection is obtained.

19. The data collection method according to claim 17 wherein the
near-infrared fluorescence intensity distribution image of the target
organ is obtained 1 to 10 days after the administration of the
indocyanine green.

20. The data collection method according to claim 17 wherein the
near-infrared fluorescence intensity distribution image of the target
organ in a living body administered with indocyanine green that is
neither complexed with a high density lipoprotein nor bound to antibodies
against proteins that are specifically present in accessory cancer
lesions is obtained.

21. The data collection method according to claim 17 wherein the cancer is
primary liver cancer or metastatic liver cancer.

22. The data collection method according to claim 17 wherein the living
body is a living body of human or non-human mammal.

23. An accessory cancer lesion detector that detects an accessory cancer
lesion during surgery for shrinking, destruction, or resection of a
cancer lesion, comprisingan irradiation means for irradiating indocyanine
green in a target organ suspected of having cancer in a living body into
which the indocyanine green has been administered with excitation light
of indocyanine green, andan imaging means that captures the near-infrared
fluorescence intensity distribution image from the excited indocyanine
green in the target organ.

24. The accessory cancer lesion detector according to claim 23 wherein the
irradiation means and the imaging means are installed in an integrated
manner so that the detector can be brought close to the site of the
accessory lesion, which is exposed in the surgery.

25. The accessory cancer lesion detector according to claim 23 wherein the
irradiation means is a near-infrared light emitting device and the
imaging means is a solid state imager.

Description:

BACKGROUND OF THE INVENTION

[0001]1. Field of the Invention

[0002]The present invention relates to a method of detecting cancer using
an ICG fluorescence method. The present invention further relates to a
method of detecting an accessory cancer lesion and a device used thereof,
a method of treating the cancer, and an accessory cancer lesion detection
agent and composition thereof.

[0003]2. Related Background Art

[0004]Computer tomography (CT), nuclear magnetic resonance imaging (MRI),
and ultrasonographic imaging are widely used as methods of imaging a
cancer lesion. For example, contrast CT, wherein an iodinated contrast
agent having high x-ray absorption is injected into a blood vessel
(normally a peripheral vein), is generally used for testing cancer by CT
(see, for example, National Publication of International Patent
Application No. 2007-533737).

SUMMARY OF THE INVENTION

[0005]However, even when the cancer lesion is identified by a method
described above, or any other known imaging method, and resected, this
does not lead to complete cure of the cancer in many cases.

[0006]For example, the 5-year recurrence-free survival of patients who
have undergone radical resection of hepatocellular carcinoma (HCC) is as
low as about 30%. One suspected reason for this low survival, especially
in cases of early recurrence that occurs within 2 years post surgery is
that the accessory cancer lesion that cannot be detected by conventional
preoperative examination or intraoperative macroscopic observation is
missed in the resection. Thus, there is a need to improve the sensitivity
of detecting the accessory lesion before and during the surgery, in order
to completely cure the cancer.

[0007]The object of the present invention is therefore to provide a
detection method that enables the detection of an accessory cancer
lesion.

[0008]The present invention provides a method of detecting an accessory
cancer lesion, comprising an administration step wherein indocyanine
green (ICG) is administered to a living body, an irradiation step wherein
a target organ suspected of having cancer is surgically exposed and
irradiated with indocyanine green excitation light, an imaging step
wherein a near-infrared fluorescence intensity distribution image from
the excited indocyanine green in the target organ is obtained, and an
identification step wherein an area having the near-infrared fluorescence
in the intensity distribution image, excluding the area detected in
preoperative examination or intraoperative macroscopic observation, is
identified as an accessory cancer lesion.

[0009]By employing this method, an accessory cancer lesion can be detected
intraoperatively in an area where it has not been detected by x-ray (CT),
MRI, ultrasonography, or macroscopic observation of the target organ.
Therefore, the method can prevent the missing of a minute accessory
cancer lesion during surgery, and improve postoperative survival. In the
present invention, the lesion detected by preoperative examination
(x-ray, MRI, ultrasonography, etc) or through intraoperative macroscopic
observation is termed "main cancer lesion".

[0010]A conventional test for liver function is performed wherein
indocyanine green (a dye) is injected into a vein in the arm, blood is
collected after the lapse of a certain time, the residual dye in the
blood is quantitatively determined, and the amount of dye processed by
the liver is calculated. However, the present inventors were the first to
discover the phenomenon of intravenously injected indocyanine green that
is neither complexed with a high density lipoprotein nor has antibodies
against proteins specifically present in cancer tissue, accumulating to
detectable levels not only in the main lesion but also in the accessory
lesion.

[0011]The application of the above-described method provides an excellent
method of treating cancer. In short, a method of treating cancer by
shrinking, destroying or resecting an area containing at least one
accessory lesion identified by the method of detecting an accessory
cancer lesion can be provided.

[0012]It became clear from the above finding that the indocyanine green
functions as a detection agent for an accessory cancer lesion. In other
words, the indocyanine green that is neither complexed with a high
density lipoprotein nor bound to antibodies against proteins specifically
present in an accessory lesion effectively functions as an accessory
cancer lesion detection agent.

[0013]The indocyanine green need not be used alone; it can be used in the
form of a distilled water-containing composition, for detecting an
accessory cancer lesion.

[0014]In other words, the use of the indocyanine green, or a composition
containing indocyanine green and distilled water, for detecting an
accessory cancer lesion is provided.

[0015]Further, the present invention provides a data collection method
comprising comparing a near-infrared fluorescence intensity distribution
image obtained by irradiating the target organ in a living body into
which indocyanine green has been administered with indocyanine green
excitation light, with a cancer lesion distribution image obtained by the
use of x-rays, nuclear magnetic resonance or ultrasound on the target
organ before administering the indocyanine green, and collecting the data
of an area that is detected in the near-infrared fluorescence intensity
distribution image but not in the cancer lesion distribution image as
accessory cancer lesion area data.

[0016]According to this method, the data on the accessory cancer lesion
(including boundary information, such as location, size, etc, of the
accessory cancer lesion) can be collected from an area of the target
organ that are not detected by x-ray CT, MRI, ultrasonography, or
macroscopic observation. In other words, the data collection method of
the present invention is a method of collecting data on a human body for
assisting the final diagnosis. The use of such data can prevent the
missing of a minute accessory cancer lesion by doctors, and improve the
postoperative survival of the patient. In the present invention, a lesion
detected in the cancer lesion distribution images obtained by the use of
x-rays, MRI, or ultrasound on the target organ before administering the
indocyanine green is termed "main cancer lesion".

[0017]It is preferable to obtain the near-infrared fluorescence intensity
distribution image of the target organ after intravenous injection of
indocyanine green, and it is preferable to obtain the intensity
distribution image of the target organ 1 to 10 days after indocyanine
green administration.

[0018]Furthermore, it is preferable to obtain the near-infrared
fluorescence intensity distribution image of the target organ in a living
body administered with indocyanine green that is neither complexed with a
high density lipoprotein nor bound to antibodies against proteins
specifically present in an accessory cancer lesion. However, the
near-infrared fluorescence intensity distribution image can also be
obtained from a target organ in a living body to which indocyanine green
in the form of the above-described complex, or indocyanine green bound to
the above-described antibodies, has been administered.

[0019]The device described below can be used in the above-described
accessory cancer lesion detection method and data collection method. In
other words, one can use an accessory cancer lesion detector, which
detects an accessory cancer lesion during the surgery for shrinking,
destruction, or resection of a cancer lesion, and comprises an
irradiation means for irradiating the target organ suspected of having
cancer in a living body into which indocyanine green has been
administered with indocyanine green excitation light, and an imaging
means for obtaining the near-infrared fluorescence intensity distribution
image from the excited indocyanine green in the target organ.

[0020]In this device, it is preferable that the irradiation means and
imaging means are installed in an integrated manner so that the device
can be brought close to the site of the accessory lesion exposed by the
surgery. This type of configuration enables image acquisition, for
instance, by bringing the device close to the cancer lesion after the
abdomen has been surgically opened.

EFFECT OF THE INVENTION

[0021]The present invention can provide a method of detection that enables
the detection of an accessory cancer lesion and a data collection method
for an accessory cancer lesion area, and therefore, can improve the
5-year recurrence-free survival of patients who undergo radical cancer
surgery.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022]FIG. 1 is a configuration diagram of an embodiment of the accessory
cancer lesion detector;

[0023]FIG. 2 is a perspective view showing the configuration of the
excitation light source unit and imager used in the detector shown in
FIG. 1;

[0024]FIG. 3 shows images of a cancer lesion obtained by contrast CT and
the ICG fluorescence method, and micrographs of a cancer lesion; 3A is an
image obtained by contrast CT, 3B is a near-infrared fluorescence
intensity distribution image from ICG in the liver, 3C is a micrograph of
a tissue section of an accessory lesion, and 3D is a magnified image of
the micrograph of 3C;

[0025]FIG. 4 shows images of a cancer lesion obtained by contrast CT and
the ICG fluorescence method, and micrographs of a cancer lesion; 4A is an
image obtained by contrast CT, 4B is a near-infrared fluorescence
intensity distribution image from ICG in the liver, 4C is a micrograph of
a tissue section of an accessory lesion, and 4D is a magnified image of
the micrograph of 4C;

[0026]FIG. 5 shows images of a cancer lesion obtained by contrast CT and
the ICG fluorescence method, and micrographs of a cancer lesion; 5A is an
image obtained by contrast CT, 5B and 5C are near-infrared fluorescence
intensity distribution images from ICG in the liver, and 5D is a
micrograph of a tissue section of an accessory lesion;

[0027]FIG. 6 shows images of a cancer lesion obtained by contrast CT and
the ICG fluorescence method, photographs of a resected cancer lesion, and
micrographs of a cancer lesion; 6A is an image obtained by contrast CT,
6B is a near-infrared fluorescence intensity distribution image from ICG
in the liver, 6C and 6G are photographs of formalin-fixed liver, 6D and
6H are near-infrared fluorescence intensity distribution images from ICG
in the resected liver (they respectively correspond to 6C and 6G), and
6E, 6F, 6I, and 6J are micrographs of lesion tissue (6F is a magnified
image of 6E and 6J is a magnified image of 6I); and

[0028]FIG. 7 shows images of a cancer lesion obtained by contrast CT and
the ICG fluorescence method, and micrographs of the cancer lesion; 7A is
an image obtained by contrast CT, 7B is a near-infrared fluorescence
intensity distribution image from ICG in the liver, 7C is a micrograph of
a tissue section of an accessory lesion, and 7D is a magnified image of
the micrograph of 7C.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029]A preferred embodiment is described below, referring to the
drawings. In the description of the drawings, identical symbols are
assigned to the same components, and duplication of descriptions is
avoided. Furthermore, parts of the drawings are exaggerated to facilitate
better understanding, and the dimensional proportions do not always match
with those of the components described.

[0030]First, the method of detecting an accessory cancer lesion will be
described. The method of detecting an accessory cancer lesion of the
present invention comprises the above-described administration step,
irradiation step, imaging step, and identification step. Now a preferred
embodiment is described stepwise.

[0031]In the administration step, indocyanine green is administered to a
living body (human or non-human mammal). In this step, normally, the
indocyanine green is administered through intravenous injection, and it
is preferable for the indocyanine green used in this step to be neither
complexed with a high density lipoprotein nor bound to antibodies against
proteins specifically present in an accessory cancer lesion. Further, it
is preferable to intravenously inject the indocyanine green along with
distilled water, in the form of a composition for detecting an accessory
cancer lesion. The content of indocyanine green in the accessory cancer
lesion detecting composition can be suitably decided, taking into account
the type and stage of the cancer, and the age and body weight of patient
(or animal patient). It is preferable to carry out this step before
starting the surgery for shrinking, destruction, or resection of the
cancer.

[0032]Next, the irradiation step, wherein indocyanine green excitation
light is irradiated on the target organ suspected of having the cancer,
is carried out. Near-infrared light (700 to 1000 nm, particularly 700 to
800 nm) is preferable as the excitation light. The use of a light
emitting diode (LED) or a semiconductor laser (LD) is preferable as the
specific means in the irradiation step. Alternatively, one may use an
optical filter (such as a low pass filter that allows the passage of
light of wavelength 800 nm or less, or a band pass filter with a center
wavelength of 760 nm) fitted to a halogen lamp of about 150 W as the
excitation light source, and light from this source may be irradiated
through optical fibers. The intensity of the excitation light and the
excitation time can be decided suitably, depending on the amount of
indocyanine green introduced, the size of the cancer lesion, etc. This
step is preferably carried out after the start of the surgery for
shrinking, destruction, or resection of the cancer lesion but before
carrying out the shrinking, destruction or resection.

[0033]Next, the near-infrared fluorescence intensity distribution image
from the excited indocyanine green in the target organ is obtained in the
imaging step.

[0034]The near-infrared fluorescence from the excited indocyanine green
typically has a wavelength of 800 to 900 nm (825 to 850 nm in
particular). Therefore, the near-infrared fluorescence intensity
distribution image is obtained using an imaging means that can capture
light of the concerned wavelengths. Examples of such imaging means
include solid state imagers such as CCD cameras. When using a CCD camera,
it is preferable to remove the infrared cut filter.

[0035]The imaging step is preferably carried out 1 to 10 days, more
preferably 3 to 5 days, after the indocyanine green administration step.
If the imaging is done soon after the administration of the indocyanine
green (in less than 1 day from the administration step), sometimes,
near-infrared fluorescence is obtained from all parts of the target
organ, and there is the possibility of not being able to differentiate
the lesion from normal tissue. Beyond 10 days after the administration
step, the near-infrared fluorescence sometimes becomes faint even in the
lesion.

[0036]The present inventors do not wish to adhere to one particular
theory, but assume that the indocyanine green gets accumulated in the
neovascularized part of the cancer lesion. New blood vessels are
continuously formed one after the other in a cancer lesion. It is
conceivable that the indocyanine green can easily leak out from the newly
formed blood vessels, and therefore, it gets accumulated around the newly
formed vessels.

[0037]The imaging step is preferably carried out after the start of the
surgery for shrinking, destruction, or resection of the cancer lesion but
before carrying out the shrinking, destruction or resection. In other
words, it is preferable to do the imaging after starting the surgery for
treating the cancer, but before actually treating the cancer lesion. As
for the surgical method, resection is considered to be most suited for
the method of the present invention.

[0038]It is suitable to do the imaging 2-dimensionally or 3-dimensionally
all over the target organ. In this manner, the location of the cancer
lesion (a main lesion and/or an accessory lesion) that are the targets of
shrinking, destruction or resection can be accurately identified.

[0039]Next, the identification step is carried out. In this step, the area
having near-infrared fluorescence, other than the area of the intensity
distribution image already detected in the preoperative examination or
intraoperative macroscopic observation is identified as the accessory
cancer lesion.

[0040]In the identification step, the area, other than the area (main
lesion) detected by x-ray CT, MRI, ultrasonography, or macroscopic
observation of the target organ, can be identified as the accessory
lesion. In this case, there may be more than one accessory lesion
identified.

[0041]The cancer targeted by the present invention is preferably a solid
cancer (primary cancer) such as gastric cancer, esophageal cancer, colon
cancer, liver cancer, etc, but it can be metastatic cancers that have
metastasized from a cancer of some other organ. Among the solid cancers,
liver cancer, hepatocellular carcinoma in particular, is suitable for
applying the method of the present invention because patients of such
cancers have low postoperative survival. Furthermore, the subject (living
body) to be tested can be a human or non-human mammal.

[0042]A novel method of treating cancer, where the accessory cancer lesion
detection method of the present invention is used, is provided. In other
words, a method of treating cancer is provided, wherein the area having
at least one accessory lesion identified by the accessory cancer lesion
detection method is shrunk, destroyed, or resected. In this treatment
method, usually, the main cancer lesion is shrunk, destroyed or resected
along with the area having at least one accessory lesion.

[0043]As described above, the indocyanine green functions as the accessory
cancer lesion detection agent. In other words, the indocyanine green
functions as a detection agent that detects an accessory lesion present
in an area where no lesion is detected in the x-ray imaging, MRI,
ultrasonography, or macroscopic observation. As described for the
administration step, indocyanine green that is neither complexed with a
high density lipoprotein nor bound to antibodies against proteins
specifically present in the accessory lesion is suitable.

[0044]The accessory cancer lesion detection agent is effective for liver
cancer, especially hepatocellular carcinoma. It is preferable to
administer it to the living body (human or non-human mammal) at such a
time that the detection would be done 1 to 10 days later.

[0045]Next, the data collection method of the present invention is
described. In the data collection method of the present invention, the
near-infrared fluorescence intensity distribution image is obtained by
irradiating the target organ in the living body into which indocyanine
green has been administered with indocyanine green excitation light.
Besides this, a cancer lesion distribution image of the target organ is
obtained by the use of x-rays, nuclear magnetic resonance or ultrasound,
before administration of the indocyanine green.

[0046]The near-infrared fluorescence intensity distribution image from the
target organ of a living body to which indocyanine green has been
administered can be obtained in above-described mode.

[0047]The cancer lesion distribution image is obtained by the use of
x-rays, nuclear magnetic resonance or ultrasound to the target organ
before the indocyanine green administration. The lesion detected by such
imaging is the main cancer lesion, and the detectable size of such lesion
is about 5 mm in the long axis direction.

[0048]The cancer lesion distribution image obtained by the use of x-rays,
i.e., the x-ray image (CT), can be captured using, for instance, the
Aquilion 16 (trademark) medical x-ray CT system (manufactured by Toshiba
Medical Systems Corporation) or similar equipment. The nonlimiting
exemplified condition for capturing x-ray image (CT) of a liver is: tube
voltage 120 kV, tube current 400 mA, rotation time 0.5 sec/rotation,
pitch 1.5, and slice thickness 1 mm. Examples of iodinated contrast
agents include Iopamiron (registered trademark) (Bayer HealthCare), which
has iopamidol (generic name) as the active ingredient. For instance, 370
mg (95 mL) of Iopamiron may be injected at the rate of 4 mL/sec. A scan
delay time of 20 sec may be used in case of early arterial phase
(screening), about 30 sec for late arterial phase (detailed examination),
and about 80 sec for portal venous phase (detailed examination) scanning.
The dose of the x-ray is to be set according to the size of a patient.

[0049]The cancer lesion distribution image obtained by the use of nuclear
magnetic resonance, i.e., the nuclear magnetic resonance image (MRI), can
be captured by using, for instance, the MAGNETOM Symphony 1.5T
(manufactured by Siemens AG) MRI system or similar equipment. The
procedure for capturing image is not specifically restricted and
exemplified by the following method. Firstly, before injection of the
contrast agent, slice images along the three axis directions, i.e.,
coronal, sagittal, and transverse, are acquired under the static
condition. Next, the contrast agent is injected, and dynamic imaging is
carried out. More specifically, after deciding the imaging site, a bolus
of the contrast agent is injected intravenously, and the changes with
time in the three axis directions are captured at intervals of about 10
sec. In some cases the imaging may done along one axis direction only.
Finally, after the lapse of sufficient time from the injection of the
contrast agent, slice images along the three axis directions are captured
as static contrast-enhanced images. Among these nuclear magnetic
resonance images, the dynamic images are particularly effective for
assessing the quality of a cancer lesion.

[0050]The cancer lesion distribution image obtained by the use of
ultrasound, i.e., the ultrasound image, can be captured, for instance,
using the digital diagnostic ultrasound system EUB-8500 (manufactured by
Hitachi Medical Corporation) or similar equipment. The imaging frame rate
and power level can be set by a person skilled in the art, based on the
location, size, etc of the target organ.

[0051]Data on the accessory cancer lesion area is then collected from the
two types of images obtained by the methods described above. In other
words, data on the area detected by the near-infrared fluorescence
intensity distribution image, but not detected in the cancer lesion
distribution image is collected as the data on the accessory cancer
lesion area.

[0052]The accessory cancer lesion area data can be identified by
superimposing the near-infrared fluorescence intensity distribution image
and the cancer lesion distribution image. Such superimposition can be
done manually or by superimposing digital images. The two images can be
compared, for instance, by identifying, from the cancer lesion
distribution image, the organ wherein the main cancer lesion is present,
and then determining the location of the identified organ in the
near-infrared fluorescence intensity distribution image. In other words,
the area detected in the near-infrared fluorescence intensity
distribution image but not in the cancer lesion distribution image can be
discovered. The data collection method of the present invention is
particularly useful when the accessory cancer lesion is present in an
organ that cannot be detected in the cancer lesion distribution image.
However, the method can also be used for detecting a lesion (an accessory
lesion) in parts that cannot be detected in the cancer lesion
distribution image although the organ itself can be detected in that
image. By using the data collection method of the present invention, a
cancer lesion (an accessory lesion) with a long axis length of less than
5 mm can be detected.

[0053]Next, the accessory cancer lesion detector is described. In the
above-described accessory cancer lesion detection method and data
collection method, an accessory cancer lesion detector that comprises at
least an irradiation means and an imaging means can be used for detecting
an accessory cancer lesion during surgery for shrinking, destruction, or
resection of a cancer lesion.

[0054]FIG. 1 is a configuration diagram of an embodiment of such an
accessory cancer lesion detector. FIG. 2 is a perspective view showing
the configuration of the excitation light source unit and imager used in
the accessory cancer lesion detector shown in FIG. 1.

[0055]The accessory cancer lesion detector of the embodiment shown in FIG.
1 irradiates the excitation light 10 of a certain wavelength on to the
target organ 20, and observes the image created by the fluorescence
(fluorescence image 11) emitted by the target organ 20, to detect the
accessory cancer lesion. In the detection of an accessory cancer lesion
using this detector, indocyanine green is injected beforehand at a point
near the lesion in the target organ 20, or intravenously. Then, the
near-infrared fluorescence coming from the indocyanine green accumulated
in the accessory cancer lesion is observed to detect the accessory cancer
lesion.

[0056]The accessory cancer lesion detector shown in FIG. 1 comprises the
excitation light source unit 2 (irradiation means), optical filter 3,
imager 4 (imaging means), controller 5, and image display device 6. The
excitation light source unit 2 has a plurality of excitation light
sources 2a, and a support 2b on one side whereof the excitation light
sources 2a are installed. Each of the excitation light sources 2a
comprises a light source that radiates light of the same wavelength as
the excitation light, and is used to irradiate the target organ 20 with
the excitation light 10. As shown in FIG. 2, the excitation light sources
2a are arranged two-dimensionally with symmetry about the central axis Ax
of the excitation light source unit 2, which will become the optical axis
of the detector.

[0057]As mentioned earlier, it is preferable to use semiconductor lasers
(LD) or light emitting diodes (LED) as the excitation light sources 2a.
The wavelength of the excitation light 10 supplied by the excitation
light source 2a is suitably selected (760 nm for instance) from the
near-infrared wavelength band, as the absorption band of indocyanine
green is in that range.

[0058]An opening 2c is provided on the support 2b at its central location,
which includes the central axis Ax. The opening 2c is provided for the
passage of the fluorescence image 11, which comes from the target organ
20 towards the front of the excitation light source unit 2, to pass to
its rear. The plurality of excitation light sources 2a described above is
aligned 2-dimensionally to surround the opening 2c. In such a
configuration, it is suitable to set the optical axes of those excitation
light sources 2a located close to the opening 2c inclined towards the
central axis Ax to prevent the intensity distribution of the excitation
light 10 irradiated on to the target organ 20 from becoming weak at the
center because of the effect of the opening 2c.

[0059]An optical filter 3 is installed in the opening 2c of the support
2b. This optical filter 3 allows the passage of light of the wavelength
band of the fluorescence image 11 emitted by the accessory cancer
lesions, out of the light coming from the target organ 20, which is the
object of observation. A filter having transmission characteristics that
cut off light of wavelengths other than that of the fluorescence image
11, which includes the excitation light 10 reflected back by the target
organ 20, is preferably used as the optical filter 3.

[0060]The imager 4 is installed at the rear of the excitation light source
unit 2. In this embodiment, the imager 4 is integrated with the
excitation light source unit 2, with a common optical axis Ax. The
fluorescence image 11 emitted by the fluorescent dye in an accessory
cancer lesion, which is excited by the excitation light 10 irradiated by
the excitation light sources 2a, passes through the opening 2c and the
optical filter 3 of the support 2b, and arrives at the imager 4. The
imager 4 captures the incoming fluorescence image 11 and outputs, as
image data, the observed image thus obtained.

[0061]A CCD camera that can capture 2-dimensional images is used, for
instance, as the imager 4. The imager preferably has the capability to
capture, with high sensitivity, the light of the wavelength band of the
fluorescence image 11 (the near-infrared wavelength band, as usually the
target is a fluorescence image of about 800 nm). A power source for the
excitation light sources and a power source for the imager are connected
respectively as required with the plurality of excitation light sources
2a and the imager 4. The power sources, etc are not shown in FIG. 1.
These devices can also be battery-driven.

[0062]A controller 5 is provided for the observed image output from the
imager 4. The controller 5 is a means of manually or automatically
controlling the image data of the observed image output by the imager 4.
The controller 5 in this embodiment has a brightness control 5b and
contrast control 5c, which respectively control the brightness and
contrast of the observed image output by the imager 4. The control
settings of the observed image, in the controls 5b and 5c, are input from
the control panel 5a. The control panel 5a sets the control settings of
the observed image automatically or through inputs from the viewer. If
the control settings are fixed, there is no need to provide the control
panel 5a. The transmission of image data from the imager 4 to the
controller 5 can be through a cable, or wireless.

[0063]An image display device 6 and image recorder 7 are connected to the
controller 5. The image display device 6 displays, on its display section
6a, the observed image 15 that has been controlled by the controller 5,
as the image to be used for detecting an accessory cancer lesion.
Examples of image display devices 6 include a CRT monitor and a liquid
crystal display, attached to a CCD camera used as the imager 4. The image
recorder 7 is a means of recording the observed image data controlled by
the controller 5. Examples of devices that can be used as the image
recorder 7 include a videotape recorder that records the observed image
on videotape, a recording medium.

[0064]Now the method of detecting an accessory cancer lesion using the
accessory cancer lesion detector illustrated in FIG. 1 is described.
First, the fluorescent dye indocyanine green is injected intravenously.
After the lapse of a certain time (typically 1 to 10 days from the
intravenous injection), when excitation light 10 of a certain wavelength
(760 nm for instance) is irradiated on the target organ 20 from the
excitation light source unit 2, a fluorescence image 11 in the
near-infrared wavelength band is emitted by the accessory cancer lesion
because of the indocyanine green. Here, the optical filter 3 allows the
passage of the fluorescence image 11 while cutting off the reflected
light coming from the target organ 20 that is being irradiated by the
excitation light 10.

[0065]The fluorescence image 11 that passes through the optical filter 3
is captured by the CCD camera used as the imager 4, and the data of the
observed image is output from the CCD camera to the controller 5. The
controller 5 controls the brightness and contrast of the observed image
coming from the imager 4. As a result, the observed image 15 (which
includes the image of the main cancer lesion) containing the accessory
cancer lesion image 16 is generated. When such an image is displayed on
the display section 6a of the image display device 6, the detection of
the accessory cancer lesion is realized. Furthermore, if necessary, the
observed image 15 is recorded on a recording medium in the image recorder
7.

[0066]The accessory cancer lesion area data can be collected by comparing
the near-infrared fluorescence intensity distribution image, obtained as
described above, with the cancer lesion distribution image obtained by
the use of x-rays, nuclear magnetic resonance, or ultrasound on the
target organ 20 before administering the indocyanine green.

EXAMPLES

[0067]The present invention will now be described in more specific terms,
citing some examples of the present invention. However, these examples in
no way restrict the scope of the invention, and various modifications can
be made within the technical scope of the present invention.

[0068]In the examples 1 to 5 given below, the ICG (0.5 mg/kg) was injected
intravenously a few days before the surgery. In other words, in the
examples 1, 2, 3, 4, and 5, the intravenous ICG injection was
administered, respectively, 4, 4, 8, 1, and 4 days before the surgery.
The liver was observed with he infrared camera system PDE (Photodynamic
Eye (trade name), Hamamatsu Photonics K.K.) having the configuration
shown in FIGS. 1 and 2, used as the accessory cancer lesion detector, and
hepatocellular carcinoma was detected. In examples 1 to 4, the cancer was
primary liver cancer, and in Example 5 it was metastatic liver cancer.

Example 1

[0069]Example 1 was a case of a male in his 50s. Preoperative contrast CT
detected the presence of a single HCC, 40 mm in diameter, in the S5/8
segment of the liver. FIG. 3A is an image showing the result of contrast
CT. The arrow indicates the HCC. When the patient's abdomen was cut open
and intraoperative diagnosis was carried out with the PDE, a fluorescent
area, 5 mm in diameter, was detected in the S4 segment of the liver, in
addition to the main tumor (main lesion). Therefore, this part (the
accessory lesion) was also resected. FIG. 3B is a near-infrared
fluorescence intensity distribution image (measured after the abdomen was
opened but before the resection) from ICG in the liver. The arrow
(arrowhead) at right indicates the fluorescent area (accessory lesion), 5
mm in diameter, in the S4 segment of the liver. The larger fluorescent
area, indicated by the arrow on the left, is the main tumor area (main
lesion). Based on histological tests on the resected tissue, the main
tumor was diagnosed as moderately differentiated HCC, and the accessory
lesion detected in the S4 segment of the liver was diagnosed as highly
differentiated HCC. FIG. 3C is a micrograph of a tissue section of the
accessory lesion (fluorescent area, 5 mm in diameter, in the S4 segment
of the liver), and FIG. 3D is a magnified image of the micrograph of FIG.
3C.

Example 2

[0070]Example 2 was a case of a male in his 70s. Preoperative contrast CT
detected the presence of a single HCC, 45 mm in diameter, in the S2/3/4
segment of the liver. FIG. 4A is an image showing the result of contrast
CT. The arrow indicates the HCC. From the contrast CT image, the HCC was
diagnosed to be simple nodular type. But after opening of the abdomen,
and intraoperative diagnosis using the PDE, some fluorescent areas
(accessory lesions), 2 to 3 mm in diameter, were detected scattered
around the main tumor (main lesion). Therefore, the area to be resected
was made to include these, and the resection was carried out. FIG. 4B is
a near-infrared fluorescence intensity distribution image (measured after
the abdomen was opened but before the resection) from ICG in the liver.
The fluorescent area indicated by the arrow at right is the main tumor
area (main lesion). The two arrows (arrowheads) at left indicate
fluorescent areas (accessory lesions), 2 to 3 in mm diameter, seen around
the main tumor. Based on histological tests on the resected tissue, the
main tumor was diagnosed to be a moderately differentiated HCC, and the
scattered nodules (accessory lesions) were diagnosed to be satellite
nodules of simple nodular HCC with extranodular growth. FIG. 4C is a
micrograph of a tissue section of an accessory lesion (fluorescent area,
2 to 3 mm in diameter seen around the main tumor), and FIG. 4D is a
magnified image of the micrograph of FIG. 4C.

Example 3

[0071]Example 3 was a case of a male in his 60s. Preoperative contrast CT
detected the presence of a single HCC, 25 mm in diameter, in the S8
segment of the liver. FIG. 5A is an image showing the result of contrast
CT. The arrow indicates the HCC. When the abdomen was opened, the surface
of the liver was found to be irregular. Therefore, the identification of
the main tumor (main lesion) by intraoperative ultrasonography diagnosis
was difficult. But intraoperative diagnosis using the PDE could confirm
the HCC areas (main and accessory lesions) as fluorescent areas, which
made it easy to decide the area to be resected. FIG. 5B and FIG. 5C are
near-infrared fluorescence intensity distribution images (measured after
the abdomen was opened but before the resection) from ICG in the liver.
The arrow in FIG. 5B indicates the main tumor (main lesion), and the
arrow (arrowhead) in FIG. 5C indicates a fluorescent area (accessory
lesion), 5 mm in diameter, in the S5 segment of the liver. Based on these
measurements, the fluorescent area (accessory lesion), 5 mm in diameter,
in the S5 segment of the liver was also resected in addition to the main
tumor (main lesion). Based on histological tests on the resected tissue,
the main tumor (main lesion) was diagnosed to be a highly differentiated
HCC, and the accessory lesion in the S5 segment was diagnosed as slightly
less differentiated HCC than the main tumor. FIG. 5D is a micrograph of
the accessory lesion (arrowhead).

Example 4

[0072]Example 4 was a case of a male in his 70s. Preoperative contrast CT
detected the presence of a single HCC, 25 mm in diameter, in the S5
segment of the liver. FIG. 6A is an image showing the result of contrast
CT. The arrow indicates the HCC. When the abdomen was opened, the surface
of the liver was found to be irregular, and the identification of the
main tumor by intraoperative ultrasonography diagnosis was difficult. But
intraoperative diagnosis by the PDE could confirm the HCC areas (main and
accessory lesions) as fluorescent areas, which made it easy to decide the
area to be resected. FIG. 6B is a near-infrared fluorescence intensity
distribution image (measured after the abdomen was opened but before the
resection) from ICG in the liver. The fluorescent area indicated by the
arrow at left is the main tumor area (main lesion), and the two arrows
(arrowheads) on the right indicate fluorescent areas (accessory lesions),
3 mm in diameter, observed around the main tumor. Based on the above
measurements, more than one fluorescent area (accessory lesions), each 3
mm in diameter, were resected in addition to the main tumor (main
lesion). Further, the resected liver was fixed in formalin and made into
3 mm thick slices (FIG. 6C and FIG. 6G), and the cross-sections observed
with the PDE (FIG. 6D and FIG. 6H). Based on histological test of the
part corresponding FIG. 6C and FIG. 6D, the main tumor and the scattered
nodules were diagnosed as highly differentiated HCC. FIG. 6E is a
micrograph of a tissue section of an accessory lesion (fluorescent area,
3 mm in diameter), and FIG. 6F is a magnified image of the micrograph of
FIG. 6E. The near-infrared fluorescence intensity distribution image of
the part corresponding the area shown in FIG. 6G (FIG. 6H) revealed light
emission from areas where no nodule was detected macroscopically (double
arrowheads in FIG. 6H). Based on histological test of the areas indicated
by the double arrowheads in FIG. 6H, these areas were also diagnosed as
highly differentiated HCC. FIG. 6I is a micrograph of tissue section
showing these parts, and FIG. 6J is a magnified image of the micrograph
of FIG. 6I.

Example 5

[0073]Example 5 was a case of a male in his 50s. Preoperative contrast CT
detected the presence of a liver tumor, 25 mm in diameter, in the S2
segment and a liver tumor, 22 mm in diameter, in the S7 segment of the
liver. FIG. 7A is an image showing the result of contrast CT. The arrow
indicate liver tumor. When the abdomen was opened, and the PDE was used
intraoperatively, apart from the two lesions identified before the
surgery, a fluorescent area (accessory lesion), 5 mm in diameter, was
also detected in the S4 segment of the liver, which was difficult to
identify definitely by palpation or intraoperative ultrasonography.
Therefore, all these areas were included in the area to be resected, and
liver resection performed. FIG. 7B is a near-infrared fluorescence
intensity distribution image (measured after the abdomen was opened but
before the resection) from ICG in the liver. The arrow (arrowhead)
indicates a fluorescent area (accessory lesion), 5 mm in diameter.
Histological test of the resected tissue confirmed that it had
adenocarcinoma, which was diagnosed as metastasis of colon cancer into
the liver. FIG. 7C is a micrograph of a tissue section of the accessory
lesion (fluorescent area, 5 mm in diameter), and FIG. 7D is a magnified
image of the micrograph of FIG. 7C.

[0074]In all the cases examined, minute HCC or metastatic cancers, which
could not be confirmed by conventional contrast CT, could be discovered
by intraoperative diagnosis with a PDE. Such minute HCC or metastatic
cancers were the ones that would have been missed in conventional
hepatectomy. Such missing is believed to be one of the reasons for the
poor 5-year recurrence-free survival.

[0075]The ICG infrared camera system described above would be useful not
only for intraoperative detection of minute HCC and metastatic cancer but
also for determining the liver resection line, and for modifying the
surgical technique.